Drugs for chronic pains

ABSTRACT

Nitro-oxyderivative compounds or salts thereof having the following general formula (I): A-(B) b0 —(C) c0 —NO 2  wherein: c0 is an integer and is 0 or 1, b0 is an integer and is 0 or 1, A=R-T 1 -, wherein R is the radical of an analgesic drug for the chronic pain, in particular for the neuropathic pain; B is such that its precursor is selected from aminoacids, hydroxyacids, polyalcohols, compounds containing at least one acid function; C is a bivalent radical containing an aliphatic, heterocyclic or aromatic radical.

The present invention relates to compounds having an improved efficacyin the reduction of the chronic pain, specifically the neuropathic pain.

For the description of the chronic pain, for simplicity, reference ismade, from now on, to the neuropathic pain.

It is known that the neuropathic pain is a form of chronic painoriginated from a damage or from a disease of the central or peripheralnervous system. The neuropathic pain comprises a series of painfulsymptomatologies, such for example the following: the diabeticneuropathic pain, the painful post-infarct syndrome, the pain caused bythe chemotherapeutic treatment, or it can derive from an infectioncaused by viral agents, such for example herpes, for instance Herpeszoster, etc.

The neuropathic pain generally afflicts the patients for years since thetherapies with conventional analgesic drugs are not effective.Furthermore it is a social problem since the neuropathic pain besidesthe physical trouble causes in the patients a serious psychologicalstress.

In the last twenty years the research on the pathogenesis of theneuropathic pain has achieved significant progress. Studies carried outon human and animal experimental models of neuropathic pain, have shownthat the central nervous system reacts to the algogen stimuli with aseries of biochemical and physiopathological responses. This capabilityof the nervous system to functionally and morphologically adapt itselfwith algogen stimuli, is known as neuroplasticity and it has anessential role in inducing the onset or in maintaining the painfulsymptomatology.

Among the drugs used in the neuropathic pain treatment the carbamazepinehas been widely used in clinical studies, and the results obtained haveshown the efficacy of said drug in the treatment of trigeminalneuralgia, of the diabetic neuropathic pain and in the post-herpeticneuralgia. However the administration of this drug produces in patientsmarked side effects such as for example, somnolence, dizziness, ataxy,nausea and vomit, which limit the use thereof.

In these last years other drugs for the treatment of the neuropathicpain have been experimented. Among these, it is in particular mentionedgabapentin, which has a high analgesic efficacy for the neuropathic paintreatment, particularly the diabetic neuropathic pain and thepost-herpetic pain. However the therapy with gabapentin causes sideeffects of central type such as somnolence, weariness, obesity, etc.(Martindale XXXth Ed. p. 374).

The need was therefore felt to have available drugs having in thetreatment of the chronic pain, in particular neuropathic pain, animproved pharmacotherapeutic profile and/or lower side effects.

It has now been surprisingly and unexpectedly found that this technicalproblem can be solved with the class of drugs which is describedhereunder.

An object of the present invention are nitrooxyderivative compounds orsalts thereof having the following general formula (I):A-(B)_(b0)—(C)_(c0)—NO₂   (I)wherein:

-   c0 is an integer and is 0 or 1, preferably 1;-   b0 is an integer and is 0 or 1, with the proviso that c0 and b0    cannot be contemporaneously equal to zero;-   A=R-T₁-, wherein R is the radical of an antipain drug for the    chronic pain, in particular for the neuropathic pain;-   T₁=(CO)_(t) or (X)_(t′), wherein X═O, S, NR_(1C), R_(1C) is H or a    linear or branched alkyl, having from 1 to 5 carbon atoms, t and t′    are integers and equal to zero or 1, with the proviso that t=1 when    t′=0; t=0 when t′=1;-   B=-T_(B)-X₂-T_(BI)- wherein-   T_(B) and T_(BI) are equal or different;-   T_(B)=(CO) when t=0, T_(B)=X when t′=0, X being as above;-   T_(BI)=(CO)_(tx) or (X)_(txx), wherein tx and txx have the value of    0 or 1; with the proviso that tx=1 when txx=0; and tx=0 when txx=1;    X is as above;-   X₂, bivalent radical, is such that the corresponding precursor of    B-T_(B)-X₂-T_(BI)- wherein the free valences of T_(B) and of T_(BI)    are saturated each with OZ, with Z or with

—N(Z^(I))(Z^(II)), being:

-   -   Z=H, C₁-C₁₀, preferably C₁-C₅ alkyl linear or branched when        possible,    -   Z^(I), Z^(II) equal to or different have the values of Z as        above, depending on that T_(B) and/or T_(BI)=CO or X, in        function of the values of t, t′, tx and txx;        the precursor compound of B as above defined is preferably        selected from the following classes of compounds:    -   aminoacids, selected from the following: L-carnosine, anserine,        selenocysteine, selenomethionine, penicillamine,        N-acetylpenicillamine, cysteine, N-acetylcysteine, glutathione        or esters thereof, preferably ethyl or isopropyl ester;    -   hydroxyacids, selected from the following: gallic acid, ferulic        acid, gentisic acid, citric acid, caffeic, dihydrocaffeic acid,        p-cumaric acid, vanillic acid;    -   aromatic and heterocyclic polyalcohols, selected from the        following: nordihydroguaiaretic acid, quercetin, catechin,        kaempferol, sulfurethyne, ascorbic acid, isoascorbic acid,        hydroquinone, gossypol, reductic acid, methoxyhydroquinone,        hydroxyhydroquinone, propyl gallate, saccharose,        3,5-di-tertbutyl-4-hydroxybenzylthio glycolate, p-cumaric        alcohol, 4-hydroxy-phenylethylalcohol, coniferyl alcohol,        allopurinol; compounds containing at least one free acid        function, selected from the following: 3,3′-thiodipropionic        acid, fumaric acid, dihydroxymaleic acid, edetic acid;        C=bivalent radical -T_(C)-Y— wherein    -   when b0=c0=1: T_(C)=(CO) when tx=0, T_(C)=X when txx=0, X being        as above defined,    -   when b0=0: T_(C)=(CO) when t=0, T_(C)=X when t′=0, X being as        above defined,    -   when c0=0: tx=0, T_(BI)=X=—O—;        Y has one of the following meanings:    -   nIX is an integer from 0 to 5, preferably 1;    -   nIIX is an integer from 1 to 5 preferably 1;    -   R_(TIX), R_(TIX′), R_(TIIX), R_(TIIX′), equal to or different        from each other are H or linear or branched C₁-C₄ alkyl;        preferably R_(TIX), R_(TIX′), R_(TIIX), R_(TIIX′) are H;    -   Y³ is a saturated, unsaturated or aromatic heterocyclic ring        having 5 or 6 atoms, containing from one to three heteroatoms,        preferably from one to two, said heteroatoms being equal or        different and selected from nitrogen, oxygen, sulphur;        or Y can be:    -   Y₀, selected from the following:    -   an alkylenoxy group R′O wherein R′ is a linear or branched when        possible C₁-C₂₀, having preferably from 2 to 6 carbon atoms, or        a cycloalkylene having from 5 to 7 carbon atoms, in the        cycloalkylene ring one or more carbon atoms can be substituted        by heteroatoms, the ring can have side chains of R′ type, R′        being as above;        or Y is selected from one of the following groups:    -   wherein nf′ is an integer from 1 to 6 preferably from 1 to 4;    -   wherein R_(1f)═H, CH₃ and nf is an integer from 1 to 6;        preferably from 2 to 4;    -   Y_(AR), selected from:        -   Y_(AR1):        -   wherein n3 is an integer from 0 to 5 and n3′ is an integer            from 1 to 3; or        -   wherein n3 and n3′ have the above meaning.

The radical R in formula (I) is preferably that of chronic analgesicdrugs, in particular of drugs for the neuropathic pain, and it can beselected from the conventional compounds used for these applications.Tricyclic antidepressive drugs and antiepileptic drugs can be mentioned.

Preferably R is the radical of an analgesic drug, having formula II:

wherein:

-   -   W is a carbon atom or a nitrogen atom;    -   m is an integer from 0 to 2;    -   R₀═H, —(CH₂)_(n)—NHR_(1A), n being an integer from 0 to 2,        wherein    -   R_(1A)═H, —C(O)—R_(1H), —C(O)O—R_(1H), wherein        -   R_(1H) is a linear or branched C₁-C₁₀ alkyl, a phenyl or            benzyl group; or R_(1H) has one of the following meanings:        -   wherein Ry is hydrogen, a linear or branched C₁-C₁₀ alkyl, a            phenyl or benzyl group;    -   R₁═H, when W═N, R₁ is the electronic doublet on the nitrogen        atom (free valence);    -   R₂ is chosen between the following groups:        -   phenyl, optionally substituted with an halogen atom or with            one of the following groups: —OCH₃, —CF₃, nitro;        -   mono- or di-hydroxy substituted benzyl, preferably 3-4            di-hydroxy substituted benzyl;        -   amidino group: H₂N(C═NH)—;        -   the radical of formula (IIA), wherein optionally one            unsaturation of ethylene type can be present between the            carbon atoms in position 1 and 2, or 3 and 4, or 4 and 5:        -   wherein:        -   p, p₁, p₂ are integers, equal to or different from each            other and are 0 or 1;        -   p₃ is an integer from 0 to 10;        -   R₄ is hydrogen, linear or branched C₁-C₆ alkyl, free            valence;        -   R₅ can have the following meanings:            -   linear or branched C₁-C₆ alkyl,            -   C₃-C₆ cycloalkyl,            -   free valence,            -   OR_(A), wherein R_(A) has the following meanings:                -   linear or branched C₁-C₆ alkyl optionally                    substituted with one or more halogen atoms,                    preferably F,                -   phenyl, optionally substituted with one halogen atom                    or with one of the following groups: —OCH₃, —CF₃,                    nitro;        -   R₆, R_(6A), R₇, R₈, equal or different, are H, methyl; or            free valence;        -   with the proviso that in the radical of formula (IIA) when            one unsaturation of ethylene type between C₁ and C₂ is            present, R₄ and R₅ are free valences such as to form the            double bond between C₁ and C₂;

when the unsaturation is between C₃ and C₄, R₆ and R₇ are free valencessuch as to form the double bond between C₃ and C₄; when the unsaturationis between C₄ and C₅, R₇ and R₈ are free valences such as to form thedouble bond between C₄ and C₅;

-   -   -   Q is equal to H, OH, OR_(B) wherein R_(B) is benzyl, a            linear or branched C₁-C₆ alkyl, optionally substituted with            one or more halogen atoms, preferably F, phenyl optionally            substituted with one halogen atom or with one of the            following groups: —OCH₃, —CF₃, nitro;        -   or Q can have one of the following meanings:            -   C₃-C₆ cycloalkyl;            -   linear or branched C₁-C₆ alkyl;            -   guanidine (H₂NC(═NH)NH—);            -   thioguanidine (HNC(═S)NH—);        -   in formula (II) R₂ with R₁ and with W═C taken together form            a C₄-C₁₀, preferably C₆, saturated or unsaturated,            preferably saturated, ring.

When in formula (II) W═C, m=1 and R₀═—(CH₂)_(n)—NH₂ with n=1, R₂ and R₁with W as above defined form together the cyclohexane ring, in theradical A of formula (I) T₁=CO and the free valence of A is saturatedwith OH, the precursor drug of R is known as gabapentine;

when in formula (II) W═C, m=0 and R₀═—(CH₂)_(n)—NH₂ with n=0, R₁═H, R₂is the radical of formula (IIA) wherein p=p₁=1, p₂=p₃=0,R₄═R₅═R₆═R_(6A)═H, Q=H, in the radical A of formula (I) T₁=CO and thefree valence of A is saturated with OH, the precursor drug of R is knownas norvaline;

when in formula (II) W═C, m=0 and R₀═—(CH₂)_(n)—NH₂ with n=0, R₁═H, R₂is the radical of formula (IIA) wherein p=p₁=1, p₂=p₃=0,R₄═R₅═R₆═R_(6A)═H, Q is the guanidine group, in the radical A of formula(I) T₁=CO and the free valence of A is saturated with OH, the precursordrug of R is known as arginine;

when in formula (II) W═C, m=0 and R₀═—(CH₂)_(n)—NH₂ with n=0, R₁═H, R₂is the radical of formula (IIA) wherein p=p₁=1, p₂=p₃=0,R₄═R₅═R₆═R_(6A)═H, Q is the thioguanidine group, in the radical A offormula (I) T₁=CO and the free valence of A is saturated with OH, theprecursor drug of R is known as thiocitrulline;

when in formula (II) W═C, m=1 and R₀═—(CH₂)_(n)—NH₂ with n=1, R₁═H, R₂is the radical of formula (IIA) wherein p=p₁=p₂=p₃=0, R₄═H, R₅=Q=CH₃, inthe radical A of formula (I) T₁=CO and the free valence of A issaturated with OH, the precursor drug of R is known as pregabaline;

when in formula (II) W═C and has configuration (S), m=1 andR₀═—(CH₂)_(n)—NH₂ with n=1, R₁═H, R₂ is the radical of formula (IIA)wherein p=p₁=p₂=p₃=0, R₄═H, R₅=Q=CH₃, in the radical A of formula (I)T₁=CO and the free valence of A is saturated with OH, the precursor drugof R is known as (S)3-isobutylGABA;

when in formula (II) W═C, m=1 and R₀═R₁═H, R₂ is the radical of formula(IIA) wherein p=p₁=1, p₂=p₃=0, R₄═R₅═R₆═R_(6A)═H, Q is the guanidinegroup, in the radical A of formula (I) T₁=NH and the free valence of Ais saturated with H, the precursor drug of R is known as agmatine;

when in formula (II) W═C, m=2 and R₀═—(CH₂)_(n)—NH₂ with n=0, R₁═H, R₂is the radical of formula (IIA) wherein p=p₁=p₂=p₃=0, R₄ and R₅ are freevalences and between C₁ and C₂ there is one ethylene unsaturation, Q=H,in the radical A of formula (I) T₁=CO and the free valence of A issaturated with OH, the precursor drug of R is known as vigabatrin;

when in formula (II) W═C m=0 and R₀═—(CH₂)_(n)—NH₂ with n=0, R₁═H, R₂ isthe radical 3-4 di-hydroxy substituted benzyl, T₁=CO and the freevalence of A is saturated with OH, the precursor drug of R is known as2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (dopa).

Other compounds used for the chronic pain which can be used asprecursors of A=R-T₁ in formula (I) are lamotrigine, topiramate,tiagabine, zonisamide, carbamazepine, felbamate, amineptine, amoxapine,demexiptiline, desipramine, nortriptyline, opipramol, tianeptine.

Generally the precursor drugs of R are synthesized according to themethods reported in “The Merck Index, 12the Ed.” (1996). When theprecursor drugs of R comprise in the molecule the radical of formula(IIA), they can be synthesized as described in patent application WO00/76958.

The precursor compounds of B of the above groups are prepared accordingto the methods known in the prior art and described, for example, in“The Merck Index, 12the Ed.” herein incorporated by reference.

Preferably when in formula (I) b0=0, Y in the bivalent linking group Cis selected between Y_(P) and Y_(AR) as above defined.

Preferably Y³ is selected from the following bivalent radicals:

The preferred of Y³ are the following: (Y12), having the two freevalences in the ortho position with respect to the nitrogen atom; (Y16)with the two valences linked to the two heteroatoms, Y1 (pyrazol)3,5-disubstituted; (Y19), wherein the free valence on the ring is foundin para position to the nitrogen atom.

The precursors of Y as defined by formula (III), wherein the freevalence of the oxygen is saturated with H and the free valence of theend carbon is saturated either with a carboxylic or hydroxyl group, areproducts available on the market or can be obtained by methods known inthe prior art.

In formula (I) the preferred precursors of B for the synthesis of thenitrooxyderivatives usable in the present invention are the following:ferulic acid, N-acetylcysteine, cysteine, caffeic acid, hydrocaffeic andgentisic acid; the preferred precursor drugs are the following:gabapentine, norvaline, arginine, pregabaline, (S)3-isobutylGABA,aginatine.

The preferred compounds of formula (I) according to the presentinvention are the following:

1-(aminomethyl)cyclohexan acetic acid2-methoxy-4-[(1E)-3-[4-(nitrooxy)butoxy]-3-oxy-1-propenyl]phenylhydrochloride ester (XV)

1-(aminomethyl)cyclohexan acetic acid 3-(nitrooxymethyl) phenylhydrochloride ester (XVI)

2-aminopentanoic acid 3-(nitrooxymethyl)phenyl hydrochloride ester(XVII)

(S)-N-acetylcysteine-, 4-(nitrooxy)butyl ester, 2-amino hydrochloridepentanoate (XVIII)

(S)-N-acetylcysteine-, 4-(nitrooxy)butyl ester,1-(aminomethyl)cyclohexanacetate hydrochloride (XIX)

1-(aminomethyl)cyclohexanacetic acid-, [6-(nitrooxymethyl)-2-pyridinyl]methyl hydrocloride ester (XX)

alpha-amino-delta-thioureidopentanoic acid, 3-(nitrooxy methyl)phenylhydrocloride ester (XXI)

(S)-N-acetylcysteine-, 4-(nitrooxy)butyl ester,alpha-amino-delta-thioureidopentanoate hydrocloride (XXII)

alpha-amino-delta-thioureidopentanoic acid,2-methoxy-4-[(1E)-3-[4-(nitrooxy)butoxy]-3-oxy-1-propenyl]phenylhydrocloride ester (XXIII)

2-amino-5-guanidinopentanoic acid, 3-(nitrooxymethyl)phenyl hydroclorideester (XXIV)

2-amino-5-guanidinopentanoic acid-,2-methoxy-4-[(1E)-3-[4-(nitrooxy)butoxy]-3-oxy-1-propenyl]phenylhydrocloride ester (XXV)

(S)-N-acetylcysteine-4-(nitrooxy)butyl ester,2-amino-5-guanidinopentanoate hydrocloride (XXVI)

4-(guanidine)butyl-3-nitrooxymethylbenzamide (XXVII)

4-(guanidine)butyl-3-[4-(4′-nitrooxybutyryloxy)-3-(methoxy)]phenyl-2-propenamidechloride (XXVIII)

1-(aminomethyl)cyclohexan acetic acid 4-(nitroxy)butyl hydrochlorideester (XXIX)

The preferred above compounds with formulas (XV) to (XXIX) can be usedas nitrate salts.

The compounds according to the present invention, when they contain inthe molecule one salifiable nitrogen atom, can be transformed into thecorresponding salts by reaction in organic solvent such for exampleacetonitrile, tetrahydrofuran with an equimolar amount of thecorresponding organic or inorganic acid.

Examples of organic acids are: oxalic, tartaric, maleic, succinic,citric acid.

Examples of inorganic acids are: nitric, hydrocloric, sulphuric,phosphoric acid.

Nitrate salts are preferred.

The compounds of the invention have shown to have an improved activityin the chronic pain treatment, in particular neuropathic, both at thecentral and peripheral nervous system level. Besides it has beensurprisingly found by the Applicant that the invention compounds notonly have an improved efficacy in reducing the neuropathic pain, butunexpectedly show also a lowering action of the progress of thepathological condition which causes the neuropathic pain. For examplewhen the drugs of the present invention are administered to diabeticpatients for reducing the diabetic neuropathic pain, it has been foundthat they are able not only to reduce neuropathies, but also to reducethe complications caused by diabetes, for example affecting the bloodvessels and/or the renal apparatus.

The compounds of the invention are particularly effective in theneuropathic pain treatment, for example the diabetic neuropathic pain,the post-infarct pain.

The compounds of the invention can also be used in combination or inadmixture with NO-donor compounds of the prior art.

Said compounds contain for example in the molecule one or more ONO₂ orONO groups.

The NO-donor compounds which can be used in combination with theinvention compounds must comply with the test in vitro definedhereinafter.

The test relates to the nitric oxide generation from the NO-donors, forexample nitroglycerin, niocorandil, nitroprussiate, etc., in thepresence of endothelial cells (method a) or platelets (method b).

a) Endothelial Cells

-   -   Human cells of the umbilical vein, cultured on plates, having a        10³ density cells/well were incubated for 5 minutes with scalar        concentrations of NO-donor (1-100 μg/ml). The incubation medium        (physiologic solution, for example Tyrode) was then analyzed to        determine the capability to generate NO of the compound under        test, by means of:    -   1) nitric oxide detection by chemiluminescence;    -   2) cGMP determination (cyclic GMP n° 2715 of the above mentioned        Merck).

For the analysis by chemiluminescence, an amount equal to 100 μl wasinjected in the reaction chamber of a chemiluminescence analyzercontaining glacial acetic acid and potassium iodide. Thenitrites/nitrates present in the medium, under these conditions areconverted into NO which is then detected after reaction with ozone,which produces light. In the equipments which measure thechemiluminescence, the luminescence produced is directly proportional tothe generated NO levels and can be measured by a suitablephotomultiplying unit of a chemiluminescence analyzer. Thephotomultiplier converts the incident light in electric voltage, whichis quantitatively recorded. On the basis of a calibration curve,prepared with scalar nitrite concentrations, it can be quantitativelydetermined the generated NO amount. For example, from the incubation of100 μM of nicorandil, an amount equal to about 10 μM of NO wasgenerated.

For cGMP determination, an aliquot of the incubation medium (equal to100 μl) was centrifuged at 1,000 revolutions per 20 seconds. Thesurnatant was removed and the sediment treated with iced phosphatebuffer (pH 7.4). The cGMP levels produced were tested by specificimmuno-enzymatic reactants. From said experiments it resulted that,under these experimental conditions, the incubation with one of thevarious tested NO-donors caused a significant increase of cGMP withrespect to the values obtained in absence of a NO-donor. For example,after an incubation with 100 μM of sodium nitroprussiate, an increase ofabout 20 times the value obtained with the incubation of the carrieralone without NO-donor was recorded.

b) Platelets

-   -   Washed human platelets, prepared substantially in the same way        as described by Radomski et al, (Br. J. Pharmacol. 92,        639-1987), were used. 0.4 ml aliquots were incubated with        NO-donor scalar concentrations (1-100 μg/ml) for 5 minutes. The        incubation medium (for example Tyrode) was then analyzed to        determine the capability of the tested compound to generate NO,        by determination of nitric oxide by chemiluminescence and the        cGMP determination, as described in the previous paragraph for        the same analyses carried out on endothelial cells. For the        determination by chemiluminescence, also in this case, on the        basis of a calibration curve prepared with scalar nitrite        concentrations, it was possible to quantitatively determine the        produced NO amount. For example, after an incubation of 100 μM        of nicorandil, an amount equal to 35 μM of NO was generated.    -   For cGMP determination, it resulted that also in these        experimental conditions the incubation with one of the tested        NO-donors gave a significant increase of cGMP with respect to        the values obtained in absence of a NO-donor. For example, after        an incubation with 100 μM of sodium nitroprussiate, an increase        of about 30 times the value obtained with the incubation of the        only carrier without NO-donor, was recorded.

The preferred NO-donor compounds are those containing in the moleculeradicals of drugs belonging to the classes of aspirin, ibuprofen,paracetamol, naproxen, diclofenac, flurbiprofen. The syntheses of thesepreferred compounds are described in patent applications WO 95/30641, WO97/16405, WO 95/09831, WO 01/12584.

The compounds of the invention can be obtained by the methods describedhereafter.

If in the drug molecule more reactive groups such for example COOHand/or HX are present, they must be usually protected before thereaction according to the methods known in the prior art; for example asdescribed in the volume by The. W. Greene: “Protective groups in organicsynthesis”, Harward University Press, 1980.

The acylhalides are prepared according to the methods known in the priorart, for example by thionyl or oxalyl chloride, halides of P^(III) orP^(V) in solvents inert under the reaction conditions, such as forexample toluene, chloroform, DMF, etc.

-   -   1) When in formula (I) b0=0 and the free valence of the radical        R of the drug is saturated with a carboxylic group, the        synthesis methods to obtain the corresponding        nitrooxyderivatives are the following:    -   1.A) The drug of formula RCOOH is treated with an agent        activating the carboxyl group selected from N,N′carbonyldi        imidazol (CDI), N-hydroxybenzotriazol and        dicyclohexylcarbodiimide (DCC) in solvent such as for example        DMF, THF, chloroform, etc., at a temperature in the range from        −5° C. to 50° C. and reacted in situ with a compound HO-Y-Hal,        wherein Y and Hal are as above defined.        DCC, HO—Y-Hal        RCOOH→R—CO—O—Y-Hal   (1C)    -   1.B) In alternative, the drug acylhalide is reacted with a        compound HO—Y—R_(8A), wherein Y is as above, R_(8A) is OH or a        halogen in the presence of a base, in an organic solvent inert        under the reaction conditions according to the scheme below        reported:        RCOHal+HO—Y—R_(8A)→R—COO—Y—R_(8A)   (1D)    -   1.C) when the compounds obtained in the above reactions have        formula R—COO—Y-Hal the corresponding nitrooxyderivatives are        obtained by reacting the compound R—CO—O—Y-Hal with AgNO₃ in        organic solvent such as acetonitrile, tetrahydrofuran according        to the scheme:        R—COO—Y-Hal+AgNO₃→R—COO—Y—ONO₂    -   1.D) When the compounds obtained in the above reactions have        formula R-COO-Y-OH the hydroxyl group is subjected to        halogenation, for example with PBr₃, PCl₅, SOCl₂, PPh₃+I₂, and        then reacted with AgNO₃ in organic solvent such as acetonitrile,        tetrahydrofuran.    -   2) When in formula (I) b0=0, and the reactive function of the        drug is the group NH₂, the synthesis methods to obtain the        corresponding nitrooxyderivatives are the following:    -   2.a) By reaction of the drug R—NH₂ with an acyl halide of        formula Hal-Y—COHal, wherein Y and Hal are as above, according        to the scheme:        R—NH₂+Hal-Y—COHal→R—NHCO—Y-Hal   (2A)    -   2.b) By reaction of the drug R—NH₂ with an acyl halide of        formula OH—Y—COHal, wherein Y and Hal are as above, according to        the scheme:        R—NH₂+Hal-Y—COCl→R—NHCO—Y—OH   (2B)    -   2.c) When the compounds obtained in the above reactions have        formula R—NHCO—Y-Hal or R—NHCO—Y—OH the corresponding        nitrooxyderivatives are obtained as above described in 1.C and        1.D respectively.    -   3. When in formula (I) b0=c0=1, and the free valence of the        radical R of the drug is saturated with a carboxylic group, the        synthesis methods to obtain the corresponding        nitrooxyderivatives are the following:    -   3.a) Alternatively, the acyl halide of the drug and the compound        of formula HX—X₂—COOH, wherein X and X₂ are as above, are        reacted according to the methods known in the prior art, to give        the compound R—CO—X—X₂—COOH which is transformed into the        corresponding sodic salt and reacted with a compound of formula        Hal-Y—R₈ wherein Hal and Y are as above and R₈ is Cl, Br,        Iodine, OH:        R—COHal+HX—X₂—COOH→R—CO—X—X₂—COOH   (3.A)        R—CO—X—X₂—COONa+Hal-Y—R_(8A)→R—CO—X—X₂—CO—Y—R_(8A)   (3.A′)        -   When R_(8A)═OH the compound of formula (3.A′) is subjected            to halogenation as above described in 1.D; when R_(8A)=Hal            the compound of formula (3.A′) is reacted with AgNO₃ in            organic solvent such as acetonitrile, tetrahydrofuran:    -   3.b) When Y_(T) is a C₄ linear alkylene, the precursor of B of        formula HO—X₂—COOH is reacted with triphenylphosphine in the        presence of a halogenating agent such as CBr₄ or        N-bromosuccinimide in tetrahydrofuran to give the compound of        formula HO—X₂—COO(CH₂)₄Br which is reacted with the molecule of        the drug RCOOH as described in 1.A and 1C.    -   4) When in formula (I) p=1 b0=c0=1, and the reactive function of        the drug is the group NH2, the synthesis methods to obtain the        corresponding nitrooxyderivatives are the following:    -   4.a) Reaction of the drug R—NH₂ with an acyl halide of formula        HX—X₂—COHal, wherein X and X₂ are as above, according to the        methods known in the prior art, to give the compound        R—NH—CO—X₂—XH which is reacted with a compound of formula        R_(8A)—Y—COHal wherein R_(8A) and Y are as above.        R—NH₂+HX—X₂—COCl→R—NH—CO—X₂—XH   (4.A)        R—NH—CO—X₂—XH+R_(8A)—YCO—Hal→R—NH—CO—X₂—X—CO—Y—R_(8A)   (4A′)    -   4.b) Alternatively, the drug R—NH₂ is reacted with a compound of        formula HX—X₂—COOH, wherein X and X₂ are as above, in the        presence of dicyclohexylcarbodiimide as described in 1.A, to        give the compound R—NH—CO—X₂—XH, which is reacted with a        compound of formula R_(8A)—Y—COCl wherein R_(8A) and Y are as        above defined, to give the following compound:        R—NH—CO—X₂—X—CO—Y—R_(8A) (4.B)        -   When R_(8A)═OH the compound of formula (4.B) or of formula            (4a′) is subjected to halogenation as above described in            1.D; when R_(8A)=Hal the compound of formula (4.B) is            reacted with AgNO₃ in organic solvent such as acetonitrile,            tetrahydrofuran.

When the compounds of the present invention have one or more chiralcentres, they can be used in a racemic form, as mixtures ofdiastereoisomers or enantiomers, as single enantiomers or singlediastereosisomers. If the compound shows geometric asymmetry, thecompound in the cis or trans form can be used.

The compounds object of the present invention are formulated in thecorresponding pharmaceutical compositions for pareneteral, oral andtopical use according the techniques well known in the field, togetherwith the usual excipients, see for example the volume “Remington'sPharmaceutical Sciences 15the Ed.”

The amount on a molar basis of the active principle in said formulationsis the same or lower than the maximum posology indicated for theprecursor drugs. Also higher doses can be used, considering their verygood tolerability.

The daily administrable doses are those of the precursor drugs, or incase lower. The daily doses can be found in the publications of thefield, such as for example in “Physician's Desk reference”.

A further object of the invention is the use of analgesic drugs for thetreatment of the chronic pain, in particular the neuropathic pain, incombination with NO-donor compounds as above defined.

The radicals of the conventional analgesic drugs for the chronic painhave been indicated above with R wherein the free valence is saturatedwith T_(1A), wherein T_(1A)=COZ₁ wherein Z₁.=SH, OZ, NHR_(1C), XZ,wherein Z, R_(1C) and X are as above defined.

Said compounds of formula RCOZ₁ are the precursor drugs of R.

It has been found that the combination of the precursor drugs of R incombination with the NO-donor compounds shows a synergic effect, wherebyit is possible to use a lower amount of the analgesic compound for thechronic pain, whereby the side effects are reduced.

Besides the above mentioned precursor drugs of R, the following ones canbe mentioned: lamotrigine, topiramate, tiagabime, zonisamide,carbamazepine, felbamate, amineptine, amoxapine, demexiptiline,desipramine, nortriptyline, opipramol, tianeptine, amitriptyline,butriptyline, clomipramine, dibenzepin, dimetacrine, dothiepin, doxepin,fluacizine, imipramine, iprindole, lofepramine, melitracen, noxiptilin,propizepine, protriptyline, trimipramine.

The NO-donor compounds are as above defined.

The following Examples illustrate the invention without limiting thescope thereof.

EXAMPLE 1 Synthesis of the 1-(aminomethyl)cyclohexan acetic acid2-methoxy-4-[(1E)-3-[4-(nitrooxy) butoxy]-3-oxy-1-propenyl]phenylhydrochloride ester (XV)

A) Synthesis of the 1-(N-tert-butoxycarbonylaminomethyl)cyclohexanacetic acid

To a solution of 1-(aminomethyl)cyclohexanacetic acid (10 g, 58.4mmoles) in a mixture of dioxane (100 ml) and water (150 ml),triethylamine (16.27 ml, 116.8 mmoles) and di-tert-butyldicarbonate(15.3 g, 70 mmoles) are added. The reaction mixture is left at roomtemperature, under stirring for 4 hours. After the solution has beencooled to 0° C. it is brought to pH 2 with HCl 5%. The precipitate isfiltered and dried under vacuum. 15 g of the expected product areobtained as a white solid having m.p.=125°-127° C.

B) Synthesis of2-methoxy-4-[(1E)-3-[4-(bromo)butoxy]-3-oxy-1-propenyl]phenol

To a solution of ferulic acid (11.6 g, 59.7 mmoles) in tetrahydrofuran(400 ml) tetrabromomethane (39.62 g, 119.47 mmoles) andtriphenylphosphine (31.34 g, 119.47 mmoles) are added. The obtainedmixture is kept under stirring at room temperature for 5 hours, filteredand evaporated at reduced pressure. The crude residue is purified bychromatography on silica gel eluting with n-hexane/ethyl acetate 7/3. 8g of the expected compound are obtained as a yellow solid havingm.p.=86°-89° C.

C) Synthesis of2-methoxy-4-[(1E)-3-[4-(nitrooxy)butoxy]-3-oxy-1-propenyl]phenol

To a solution of2-methoxy-4-[(1E)-3-[4-(bromo)butoxy]-3-oxy-1-propenyl]phenol (8 g, 24.3mmoles) in acetonitrile (500 ml) silver nitrate (12.25 g, 72.9 mmoles)is added. The reaction mixture is heated at 40° C. for 12 hourssheltered from light. The formed salt is removed by filtration and thesolution is evaporated at reduced pressure. The residue is purified bychromatography on silica gel eluting with n-hexane/ethyl acetate 75/25.4 g of the expected product are obtained as a yellow solid havingm.p.=65°-68° C.

D) Synthesis of the 1-(N-tert-butoxycarbonylaminomethyl)cyclohexanacetic acid2-methoxy-4-[(1E)-3-[4-(nitrooxy)butoxy]-3-oxy-1-propenyl]phenyl ester

To a solution of 1-(N-tert-butoxycarbonyl aminomethyl)cyclohexan aceticacid (2.5 g, 9.2 mmoles) in chloroform (200 ml) andN,N-dimethylformamide (3 ml),2-methoxy-4-[(1E)-3-[4-(nitrooxy)butoxy]-3-oxy-1-propenyl]phenol (3.15g, 10.1 mmoles), dicyclohexylcarbodiimide (5.7 g, 27.6 mmoles) andN,N-dimethylaminopyridine (33 mg, 0.27 mmoles) are added.

The reaction mixture is left at room temperature for 3 hours understirring, filtered and evaporated at reduced pressure. The obtainedresidue is treated with ethyl acetate and washed with water. The organicphase is dried with sodium sulphate and evaporated at reduced pressure.The residue is purified by chromatography on silica gel eluting withn-hexane/ethyl acetate 9/1. 5 g of the expected compound are obtained asan oil.

E) Synthesis of the 1-(aminomethyl)cyclohexan acetic acid2-methoxy-4-[(1E)-3-[4-(nitrooxy)butoxy]-3-oxy-1-propenyl]phenylhydrochloride ester

To a solution of 1-(N-tert-butoxycarbonylamino methyl)cyclohexan aceticacid 2-methoxy-4-[(1E)-3-[4-(nitrooxy)butoxy]-3-oxy-1-propenyl]phenylester (5 g, 8.8 mmoles) in ethyl acetate (100 ml) a solution HCl 1N inethyl acetate (50 ml) is added. The reaction mixture is left overnightat room temperature, then concentrated under vacuum to a volume of 40ml. The obtained residue is treated with ethyl ether. The precipitate isfiltered and dried under vacuum. 1.8 g of the expected compound areobtained as a white solid having m.p.=103°-105° C.

¹H-NMR (CDCl₃) ppm: 8.43 (2H, m); 7.55 (1H, d); 7.10 (3H, m); 6.34 (1H,d); 4.51 (2H, t), 4.26 (2H, t); 3.89 (3H, s); 3.12 (2H, s); 2.81 (2H,s); 1.82 (4H, m); 1.54 (10H, m).

EXAMPLE 2 Synthesis of the 1-(aminomethyl)cyclohexan acetic acid4-(nitrooxy)butyl hydrochloride ester

A) Synthesis of the 1-(N-tert-butoxycarbonylaminomethyl)cyclohexanacetic acid 4-(bromo)butyl ester

To a solution of 1-(N-tert-butoxycarbonyl aminomethyl)cyclohexan aceticacid (1 g, 3.6 mmoles) in N,N-dimethyl formamide (50 ml) cooled at 0°C., sodium ethylate (246 mg, 3.6 mmoles) is added.

The reaction mixture is left at 0° C. under stirring for 30 minutes andthen 1,4-dibromobutane (1.28 ml, 10.8 mmoles) is added. The solution isleft under stirring overnight at room temperature, then diluted withethyl ether and washed with water. The organic phase dried with sodiumsulphate is evaporated under vacuum. The obtained residue is purified bychromatography on silica gel eluting with n-hexane/ethyl acetate 8/2.0.7 g of the expected compound are obtained as an oil.

B) Synthesis of the 1-(N-tert-butoxycarbonylaminomethyl)cyclohexanacetic acid 4-(nitrooxy)butyl ester

To a solution of 1-(N-tert-butoxycarbonylamino methyl)cyclohexan aceticacid 4-(bromo)butyl ester (1 g, 2.5 mmoles) in acetonitrile (200 ml),silver nitrate (1.3 g, 7.5 mmoles) is added. The reaction mixture isheated at 80° C. for 6 hours sheltered from light. The formed salt isremoved by filtration and the solution is evaporated at reducedpressure. The residue is purified by chromatography on silica geleluting with n-hexane/ethyl acetate 8/2. 0.8 g of the expected compoundare obtained as an oil.

C) Synthesis of the 1-(aminomethyl)cyclohexan acetic acid4-(nitrooxy)butyl hydrochloride ester

To a solution of 1-(N-tert-butoxycarbonylamino methyl)cyclohexan aceticacid 4-(nitrooxy)butyl ester (0.8 g, 2.06 mmoles) in ethyl acetate (5ml), a HCl 1N solution in ethyl acetate (20 ml) is added. The reactionmixture is left for 3 hours at room temperature then is treated withn-hexane. The precipitate is filtered and dried under vacuum. 0.45 g ofthe expected compound are obtained as a white solid havingm.p.=80.3°-81.3° C.

¹H-NMR (DMSO) ppm: 8.23 (2H, s); 4.58 (2H, t), 4.09 (2H, t); 2.92 (2H,s); 2.56 (2H, s); 1.74 (4H, m); 1.44 (10H, m).

EXAMPLE 3 Synthesis of the 1-(aminomethyl)cyclohexan acetic acid3-(nitrooxymethyl)phenyl hydrochloride ester (XVI)

A) Synthesis of 3-(bromomethyl)phenol

To a solution of 3-hydroxybenzyl alcohol (4 g, 32.2 mmoles) in methylenechloride (250 ml), cooled at 0° C., tetrabromomethane (12.82 g, 38.6mmoles) and triphenylphosphine (12.67 g, 48.3 mmoles) are added. Themixture is kept under stirring at 0° C. for 10 minutes, then evaporatedat reduced pressure. The crude product is purified by chromatography onsilica gel eluting with n-hexane/ethyl acetate 8/2. 3.5 g of theexpected compound are obtained.

B) Synthesis of the 1-(N-tert-butoxycarbonylamino methyl)cyclohexanacetic acid 3-(bromomethyl) phenyl ester

To a solution of 1-(N-tert-butoxycarbonylamino methyl)cyclohexan aceticacid (2.6 g, 9.7 mmoles) in chloroform (200 ml) andN,N-dimethylformamide (2 ml), 4-(bromomethyl)phenol (2 g, 10.7 mmoli),dicyclohexylcarbodiimide (4 g, 19.7 mmoles) andN,N-dimethylaminopyridine (24 mg, 0.20 mmoles) are added. The reactionmixture is left at room temperature for 4 hours under stirring, filteredand evaporated at reduced pressure. The obtained residue is treated withethyl acetate and washed with water. The organic phase is dried withsodium sulphate and evaporated at reduced pressure. The obtained residueis purified by chromatography on silica gel eluting with n-hexane/ethylacetate 9/1. 1.4 g of the compound are obtained as an oil.

C) Synthesis of the 1-(N-tert-butoxycarbonylamino methyl)cyclohexanacetic acid 3-(nitrooxymethyl)phenyl ester

To a solution of 1-(N-tert-butoxycarbonylamino methyl)cyclohexan aceticacid 3-(bromomethyl)phenyl ester (1.4 g, 3.18 mmoles) in acetonitrile(300 ml) silver nitrate (1 g, 6.36 mmoles) is added. The reactionmixture is heated at 50° C. for 4 hours sheltered from light. The formedsalt is removed by filtration and the solution is evaporated at reducedpressure. The obtained residue is purified by chromatography on silicagel eluting with n-hexane/ethyl acetate 8/2. 0.75 g of the expectedcompound are obtained as an oil.

D) Synthesis of the 1-(aminomethyl)cyclohexan acetic acid3-(nitrooxymethyl)phenyl hydrochloride ester

To a solution of 1-(N-tert-butoxycarbonylamino methyl)cyclohexan aceticacid 3-(nitrooxymethyl)phenyl ester (0.75 g, 1.8 mmoles) in ethylacetate (5 ml), a HCl 1N solution in ethyl acetate (18 ml) is added. Thereaction mixture is left for 15 minutes at room temperature, then it istreated with n-hexane. The precipitate is filtered and dried undervacuum. 0.45 g of the expected compound are obtained as a white solidhaving m.p.=106°-108° C.

¹H-NMR (DMSO) ppm: 8.16 (3H, m); 7.52 (1H, t); 7.44 (1H,d); 7.34 (1H,s), 7.28 (1H, d); 5.65 (2H, s), 3.03 (2H, m); 2.86 (2H, s); 1.55 (10H,m).

EXAMPLE 4 Synthesis of the 2-aminopentanoic acid2-methoxy-4-[(1E)-3-[4-(nitrooxy) butoxy]-3-oxy-1-propenyl]phenylhydrochloride ester

A) Synthesis of the 1-(N-tert-butoxycarbonylamino)pentanoic acid

To a solution of 2-aminopentanoic acid (4 g, 34.14 mmoles) in dioxane(40 ml) and water (75 ml), triethylamine (9.5 ml, 68.29 mmoles) anddi-tert-butyldicarbonate (8.94 g, 49.97 mmoles) are added. The reactionmixture is left at room temperature, under stirring for 17 hours. Afterhaving cooled the solution at 0° C., it is brought to pH=2 with HCl at5%. It is extracted with ethyl acetate, the joined organic phases arewashed with water and dried with sodium sulphate.

The solvent is evaporated at reduced pressure to give the compound as anyellow oil which is used without further purification.

B) Synthesis of2-methoxy-4-[(1E)-3-[4-(bromo)butoxy]-3-oxy-1-propenyl]phenol

To a solution of ferulic acid (11.6 g, 59.7 mmoles) in tetrahydrofuran(400 ml), tetrabromomethane (39.62 g, 119.47 mmoles) andtriphenylphosphine (31.34 g, 119.47 mmoles) are added. The obtainedmixture is kept under stirring at room temperature for 5 hours, filteredand evaporated at reduced pressure. The obtained crude compound ispurified by chromatography on silica gel eluting with n-hexane/ethylacetate 7/3. 8 g of the expected compound are obtained as a yellow solidhaving m.p.=86°-89° C.

C) Synthesis of2-methoxy-4-[(1E)-3-[4-(nitrooxy)butoxy]-3-oxy-1-propenyl]phenol

To a solution of2-methoxy-4-[(1E)-3-[4-(bromo)butoxy]-3-oxy-1-propenyl]phenol (8 g, 24.3mmoles) in acetonitrile (500 ml) silver nitrate (12.25 g, 72.9 mmoles)is added. The reaction mixture is heated at 40° C. for 12 hourssheltered from light. The formed salt is removed by filtration and thesolution is evaporated at reduced pressure. The obtained residue ispurified by chromatography on silica gel eluting with n-hexane/ethylacetate 75/25. 4 g of the expected compound are obtained as a yellowsolid having m.p.=65°-68° C.

C) Synthesis of the 2-(N-tert-butoxycarbonylamino)pentanoic acid2-methoxy-4-[(1E)-3-[4-(nitrooxy)butoxy]-3-oxy-1-propenyl]phenyl ester

To a solution of 2-(N-tert-butoxycarbonylamino)pentanoic acid (0.5 g,2.3 mmoles) in chloroform (12 ml),2-methoxy-4-((1E)-3-(4-(nitrooxy)butoxy]-3-oxy-1-propenyl]phenol (0.86g, 2.76 mmoles), dicyclohexylcarbodiimide (0.52 g, 2.53 mmoles) andN,N-dimethylaminopyridine (0.03 g, 0.23 mmoles) are added. The reactionmixture is left at room temperature for 1 hour under stirring, filteredand evaporated at reduced pressure. The obtained residue is purified bychromatography on silica gel eluting with n-hexane/ethyl acetate 75/25.0.5 g of the expected compound are obtained as an oil. Yield 43%.

D) Synthesis of the 2-aminopentanoic acid2-methoxy-4-[(1E)-3-[(4-(nitrooxy)butoxy]-3-oxy-1-propenyl]phenylhydrocloride ester

To a solution of 2-(N-tert-butoxycarbonylamino) pentanoic acid2-methoxy-4-[(1E)-3-[4-(nitrooxy)butoxy]-3-oxy-1-propenyl]phenyl ester(0.28 g, 0.548 mmoles) in ethyl acetate (7 ml), a HCl solution in ethylacetate (6.8 N, 0.700 ml) is added. The reaction mixture is left 3 hoursat room temperature. The precipitate is filtered and dried under vacuum.0.1 g, of the expected compound are obtained as a white solid.

¹H-NMR (DMSO) ppm: 8.75 (3H, m); 7.62 (1H, d); 7.58 (1H, s); 7.3 (1H,d); 7.2 (1H, d); 6.72 (1H, d); 4.57 (2H, t), 4.26 (1H, t); 4.18 (2H, t);3.82 (3H, s); 1.95 (2H, m); 1.75 (4H, m); 1.45 (2H, m); 0.98 (3,H, m).

EXAMPLE F1

Evaluation of the Analgesic Activity of the Invention Compounds by the“paw-licking” test

Four groups of Swiss male mice (20-25 g, Charles River) each formed by10 animals, received by intraperitoneal injection Gabapentin (90 mg/kg)or the compound of formula (XVI) (Example 3), called NO-Gabapentin atthe doses of 50 mg/kg, in a saline solution. The control group receivedthe same volume of saline solution. One hour after the administration ofthe compound solutions, formalin (10 μl) was injected in the paw. In the15 minutes subsequent to formalin administration, for each animal, thenumber of times wherein it licked its paw was counted. The analysis wascarried out “in blind”.

The results reported in Table 1 are expressed as percentage ratiobetween the number of times wherein the “paw-licking” was observed inthe treated animals to that of the control group.

The results show that the NO-gabapentin is more active than the startingdrug in inhibiting the “paw-licking”.

EXAMPLE F2

Evaluation of the Analgesic Activity of the Drugs Used in the Chronic(Neuropathic) Pain Treatment Combined with a Nitric Oxide-Donor Drug.

Wistar adult rats weighing about 200 grams were used, in theexperimental model described by Bennett G J, Xie Y K, Pain 1988, 33(1):87-107. The pain response (withdrawal latencies) is determined 14 daysafter the ligature of the right sciatic nerve. The results obtained arereported in Table 2 and have been expressed as a percentage ratio of thedifference between the response from the intact paw and from the injuredpaw, to the response of the control animals, that have been injectedwith the carrier and undergone the nerve ligature. The groups were of 10rats each. The animals in each of the treated groups received,respectively, the following drugs at the indicated doses:

-   -   clomipramine 10 mg/kg i.p.,    -   2-acetylsalicylic acid (3-nitrooxymethyl)phenyl ester (ASA-NO)        100 mg/Kg p.o.    -   clomipramine+NO-ASA at the above indicated doses.    -   NO-ASA was prepared as described in patent application WO        97/16405.

The results are reported in Table 2 and show that the mixture of theanalgesic drug with the nitrooxyderivative synergically increases theanalgesic effect.

EXAMPLE F3

Acute Toxicity of Gabapentin and NO-Gabapentin in the Diabetic Animal

In 50 Wistar adult male rats weighing 165-190 g, diabetes was induced byinjection i.v. of a single dose of streptozocin (65 mg/kg in 1 ml/kgbuffer citrate at pH 4.5).

After one week the animals were distributed in three groups of 10 ratseach and treated per os for three days with daily doses of 100 mg/kg ofgabapentin and NO-gabapentin. The controls were treated only withstreptozocin.

Death rate was monitored for 7 days from the last treatment.

The results are indicated in Table 3.

The Table shows that death rate in the diabetic animals administeredwith NO-gabapentin is less than half with respect to the animals treatedwith gabapentin.

EXAMPLE F4

In this experiment the effect of acute administration of NO-gabapentinwas assessed and compared with that of the precursor drug, gabapentin,in a rat model of neuropathic pain.

In 6 groups of female Sprague-Dawley rats weighting 200 g,photochemically-induced ischemic spinal cord injury was producedaccording to methods described by Xu et al. Pain, 1992, 48, 279-290.Spinally-injured rats developed a chronic pain syndrome, includingmarked mechanical and cold allodynia. The rats were injured 3-6 monthsbefore the beginning of the experiment.

Each group of rats was i.p. treated, respectively, with one of thefollowing compounds using one of the above indicated doses:

-   -   NO-gabapentin at doses of 20 mg/Kg (55 μmole/Kg), or 60 mg/Kg        (167, 21 μmole/Kg), or 100 mg/kg (278, 7 μmole/Kg), dissolved in        saline, single dose, i. p.);    -   gabapentin at doses of 30 mg/Kg (175 μmole/Kg) or 100 mg/kg (584        μmole/Kg), dissolved in saline, single dose i. p.);    -   the control group received the vehicle;        The response to cold was tested by spray-applying ethyl chloride        on the shaved allodynic skin area at time 0 (i.p. injection) and        then at 30′, 120′ and 240′. The response was evaluated according        to the following score:    -   0=no response;    -   1=localized response (skin twitch and contraction), no        vocalization;    -   2=transient vocalization, moderate struggle;    -   3=sustained vocalization and aggression.

The results are reported in Table 4 and show that acute administrationof NO-gabapentin alleviated in a dose-dependent way cold allodynia.

The effect of the compounds on motor activity was also evaluated using acombined testing system as described in Hao, J. X. and Xu, X. J., Pain,1996, 66, 279-286.

Table 5 reports the results on motor performance of the same groups ofrats i.p. injected.

When the score found in the treated group is comparable to that of thecontrol groups it means that the animals of the treated group are notimpaired as to motor activity and are not sedated.

Comments on Tables 4 and 5

Table 4 shows that the effect of NO-gabapentin was significant andlasted 120 min with the dose of 60 mg/kg (167,21 μmole/Kg) and 240 minwith the dose of 100 mg/kg (278,7 μmole/Kg). The vehicle produced noeffect. Gabapentin at the dose of 30 mg/Kg (175 μmole/Kg) did notproduce a significant antiallodynic effect (Table 4). At the dose of 100mg/kg (584 μmole/Kg), induced motor impairment and sedation (Table 5),which made it difficult to evaluate its anti-allodynic effect.

EXAMPLE F5

In this experiment the effect of repeated administration ofNO-gabapentin was assessed and compared with that of the precursor druggabapentin in a rat model of neuropathic pain. In 4 groups of femaleSprague-Dawley rats weighting 200 g photochemically-induced ischemicspinal cord injury was produced according to methods describe by Xu etal. Pain, 1992, 48, 279-290.

Spinally-injured rats developed a chronic pain syndrome, includingmarked mechanical and cold allodynia. The rats were injured 3-6 monthsbefore the beginning of the experiment. Each of the groups of rats werei.p. treated daily for 10 day, respectively, with 60 mg/kg (167,2μmole/Kg) of NO-gabapentin and with 30 mg/Kg (175 μmole/Kg) ofgabapentin. Controls (two groups) received only the vehicle. Each daythe treatment of the animals was made at the same time. During theexperiment vocalized thresholds to graded mechanical touch/pressure weretested with von Frey hairs.

During testing, rats were gently restrained in a standing position andthe von Frey hair was pushed onto the skin until filament becomes bent.The frequency of stimulation was about 1/s and repeated 5-10 times. Theintensity of stimulation (g) which induced consistent vocalization (>75%response rate) is considered as pain threshold. Behavioral testings werecarried out before the daily for the control group and 1 hour afteradministration for the treated groups.

The effect of chronic daily administration of gabapentin andNO-gabapentin is reported in Table 6.

NO-gabapentin alleviated mechanical allodynia following the firstadministration and a significant effect was maintained up to day 6.Gabapentin did not produce a significant effect up to the second day andthe effect was lower than that of NO-gabapentin. TABLE 1 Evaluation ofthe analgesic activity of gabapentin and of the NO-gabapentin derivativein the experiment F1 (rats injected in a paw with formalin) Number “pawlicking” Treatment Dose (mg/kg ) % Controls 100 Gabapentin 90 80NO-Gabapentin 50 70

TABLE 2 Ex. F2: analgesic activity of the drugs used in the chronic(neuropathic) pain treatment in combination with a nitric oxide-donordrug Treatment response % Controls 100 Clomipramine 72 NO-ASA 82Clomipramine + NO-ASA 29

TABLE 3 Rex. F3: acute toxicity of gabapentin and NO-gabapentin indiabetic rats Treatment lethality % Controls 10 Gabapentin 50NO-gabapentin 20

TABLE 4 Ex. F4: effect of different doses of NO-gabapentin andgabapentin on cold stimulation in a rat model of neuropathic pain.Response is evaluated with by a score (0-3). Dose Time (min) Compound(μmole/kg) 0 30 120 240 Control — 2 2 2 2 NO-gabapentin 55.7 2 2 2 —NO-gabapentin 167.2 2 1 1 — NO-gabapentin 278.7 2 1 1 1 Gabapentin 175 22 2 2 gabapentin 584 — — — —

TABLE 5 Ex. F4: effect of different acute doses of NO-gabapentin andgabapentin on motor performance in a rat model of neuropathic pain. DoseTime (min) Compound (μmole/kg) 0 30 120 240 Control — 15 15 15 15NO-gabapentin 55.7 14 14 14 — NO-gabapentin 167.2 14 14 15 —NO-gabapentin 278.7 14 15 14 14 Gabapentin 175 20 20 20 20 Gabapentin584 15 30 30 25

TABLE 6 Ex. F5: effect of repeated administration of NO-gabapentin andgabapentin on vocalization threshold (g) to mechanical stimulation withvon Frey hairs in a rat model of neuropathic pain. Dose Day Compound(μmole/kg) 1 2 4 6 Baseline — 2 5 8 2 NO-gabapentin 167.2 100 200 400 90Baseline — 5 3 3 5 Gabapentin 175 5 6 70 90

1. Nitrooxyderivative compounds or salts thereof having the following general formula (I): A-(B)_(b0)-(T_(C)-Y)_(c0)—NO₂   (I) wherein: c0 is an integer equal to 1; b0 is an integer and is 0 or 1; A=R-T₁-, wherein the precursors of A are selected from: lamotrigine, topiramate, tiagabine, zonisamide, amineptine, demexiptiline, desipramine, nortriptyline, opipramol and tianeptine; T₁=(CO)_(t) or (X)_(t′), wherein X═O, S, NR_(1C), R_(1C) is H or a linear or branched alkyl, having from 1 to 5 carbon atoms, t and t′ are integers and equal to zero or 1, with the proviso that t=1 when t′=0; t=0 when t′=1; B=-T_(B)-X₂-T_(BI)- wherein T_(B) and T_(BI) are equal or different; T_(B)=(CO) when t=0, T_(B)=X when t′=0, X being as above; T_(BI)=(CO)_(tx) or (X)_(txx), wherein tx and txx have the value of 0 or 1; with the proviso that tx=1 when txx=0; and tx=0 when txx=1; X is as above; X₂, bivalent radical, is such that the corresponding precursor of B-T_(B)-X₂-T_(BI)- wherein the free valences of T_(B) and of T_(BI) are saturated each with OZ, with Z or with —N(Z^(I))(Z^(II)), being: Z=H, C₁-C₁₀; Z^(I), Z^(II) equal to or different have the values of Z as above, depending on that T_(B) and/or T_(BI)=CO or X, in function of the values of t, t′, tx and txx; the precursor compound of B as above defined being selected from the following classes of compounds: aminoacids, selected from the following: L-carnosine, anserine, selenocysteine, selenomethionine, penicillamine, N-acetylpenicillamine, cysteine, N-acetylcysteine, glutathione or esters thereof; hydroxyacids, selected from the following: gallic acid, ferulic acid, gentisic acid, citric acid, caffeic, dihydrocaffeic acid, p-cumaric acid, vanillic acid; and wherein when b0=c0=1, T_(C)=(CO); when tx=0, T_(C)=X, when txx=0, X being as above defined; when b0=0: T_(C)=(CO) when t=0, T_(C)=X when t′=0, X being as above defined; when c0=0: tx=0, T_(BI)=X=—O—; Y has one of the following meanings; Y_(P):

wherein: nIX is an integer from 0 to 5; nIIX is an integer comprised from 1 and 5; R_(TIX), R_(TIX′), R_(TIIX), R_(TIIX′), equal to or different from each other are H or linear or branched C₁-C₄ alkyl; Y³ is a saturated, unsaturated or aromatic heterocyclic ring, having 5 or 6 atoms, containing from one to three heteroatoms, said heteroatoms being equal or different and selected from nitrogen, oxygen, sulphur; and y³ is selected from the group consisting of:

or Y can be: Y₀, selected from the following: an alkylenoxy group R′O wherein R′ is a linear or branched when possible C₁-C₂₀ alkyl, or a cycloalkylene having from 5 to 7 carbon atoms, in the cycloalkylene ring one or more carbon atoms can be substituted by heteroatoms, the ring can have side chains of R′ type, R′ being as above; or Y is selected from one of the following groups:

wherein nf′ is an integer from 1 to 6;

wherein R_(1f)═H, CH₃ and nf is an integer from 1 to 6; Y_(AR,) selected from: Y_(AR1):

wherein n3 is an integer from 0 to 5 and n3′ is an integer from 1 to 3; or Y_(AR2):

wherein n3 and n3′ have the above meaning.
 2. Compounds according to claim 1, wherein when in formula (I) b0=0, Y in the bivalent linking group C is selected between Y_(P) and Y_(AR) as above defined.
 3. Compounds according to claim 1, wherein Y³ is selected from (Y12), having the two free valences in the ortho positions with respect to the nitrogen atom; (Y16) with the two valances linked to the two heteroatoms, Y1 (pyrazol) 3,5-disubstituted, (Y19), wherein the free valence on the ring is found in para position to the nitrogen atom.
 4. Compounds according to claim 1, wherein in formula (I) the precursors of B are the following: ferulic acid, N-acetylcysteine, cysteine, caffeic acid, hydro-caffeic and gentisic acid.
 5. Compounds according to claim 1, as nitrate salts.
 6. Compounds according to claim 1, wherein the precursor compound of B is ethyl or isopropyl ester.
 7. Compounds according to claim 1, wherein Z is a C₁-C₅ linear or branched alkyl.
 8. Compounds according to claim 1, wherein nIX is
 1. 9. Compounds according to claim 1, wherein nIIX is
 1. 10. Compounds according to claim 1, wherein R_(TIX), R_(TIX′), R_(TIIX), R_(TIIX′) are H.
 11. Compounds according to claim 1, wherein Y³ is a saturated, unsaturated or aromatic heterocyclic ring, having 5 or 6 atoms, containing one to two heteroatoms.
 12. Compounds according to claim 1, wherein Y₀ is an alkylenoxy group R′O wherein R′ is a linear or branched when possible C₂-C₆ alkyl.
 13. Compounds according to claim 1, wherein nf′ is an integer from 1 to
 4. 14. Compounds according to claim 1, wherein R_(1f)═H, CH₃ and nf is an integer from 2 to
 4. 15. Pharmaceutical compositions for parenteral, oral and topical use, comprising the compounds according to claim
 1. 16. A method of treating chronic pain, comprising administering to a subject a compound according to claim
 1. 17. The method of claim 16, wherein the chronic pain is neuropathic pain. 